WO2017019494A1 - Dispositifs orthopédiques implantables présentant des revêtements antimicrobiens - Google Patents

Dispositifs orthopédiques implantables présentant des revêtements antimicrobiens Download PDF

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Publication number
WO2017019494A1
WO2017019494A1 PCT/US2016/043533 US2016043533W WO2017019494A1 WO 2017019494 A1 WO2017019494 A1 WO 2017019494A1 US 2016043533 W US2016043533 W US 2016043533W WO 2017019494 A1 WO2017019494 A1 WO 2017019494A1
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Prior art keywords
orthopedic device
antimicrobial
antimicrobial coating
alexidine
orthopedic
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PCT/US2016/043533
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English (en)
Inventor
Nisha Gupta
Kamna GIARE-PATEL
Chuanting You
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Teleflex Medical Incorporated
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Application filed by Teleflex Medical Incorporated filed Critical Teleflex Medical Incorporated
Priority to US15/746,990 priority Critical patent/US20180221546A1/en
Priority to JP2018523377A priority patent/JP2018520838A/ja
Priority to CN201680043187.0A priority patent/CN107847647A/zh
Priority to EP16831118.1A priority patent/EP3325034A4/fr
Publication of WO2017019494A1 publication Critical patent/WO2017019494A1/fr
Priority to HK18113695.1A priority patent/HK1254710A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/206—Biguanides, e.g. chlorohexidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the present disclosure relates generally to orthopedic devices, and more particularly to implantable orthopedic devices treated with antimicrobial coatings containing alexidine to prevent infection.
  • Implanted orthopedic devices are widespread among the population today.
  • Orthopedic devices are used to replace missing joints or bone, for fixation of long bone fractures and deformities, for replacement of arthritic joints, and for other orthopedic and maxillofacial applications. Although these devices are heavily disinfected or sterilized prior to implantation, many orthopedic devices nonetheless cause serious infections in patients after they are implanted in the body. Infections of orthopedic fracture and reconstructive devices occur in approximately 5% of cases and total about 100,000 cases per year in the United States alone. Infectious agents such as Staphylococcus epidermidis and
  • Staphylococcus aureus, gram-negative bacilli and Candida species are largely responsible for the infections associated with orthopedic devices.
  • orthopedic implant-associated infections are a substantial healthcare burden, and leads to prolonged patient suffering, and substantial morbidity and even mortality.
  • chlorhexidine is commonly used as the antimicrobial agent in many antimicrobial coatings for implantable medical devices. Although chlorhexidine has been useful to some extent in medical devices, there are some serious drawbacks to chlorhexidine. For example, it is known that chlorhexidine has the ability to function as a sensitizing agent, and in rare cases it can trigger immediate hypersensitivity in the form of acute anaphylaxis.
  • chlorhexidine must be present in high concentrations in order to function as a wide spectrum antimicrobial. Such concentrations of chlorhexidine may cause skin irritation or allergic reactions in some patients. Additionally, chlorhexidine may not be as effective against some microorganisms and/or may not kill microorganisms quickly.
  • Alexidine is a disinfectant that is widely used as an antimicrobial in rinse solutions for oral and ophthalmic (for example, for contact lens cleaning and disinfecting) applications, and has been commercialized in various products, typically at levels of about 100 ppm or less for use with soft contact lenses.
  • typical concentration of alexidine is about 1%.
  • alexidine has not been used as an antimicrobial agent in antimicrobial coatings for implantable medical devices and orthopedic devices.
  • alexidine and chlorhexidine are antimicrobial agents known as bis- biguanides. Both antimicrobial agents possess the biguanide and the hexamethylene structures. Alexidine however, differs from chlorhexidine by possessing ethyl-hexyl end groups instead of chlorophenyl end groups. Due to this structural difference, alexidine is shown to produce lipid phase separation and domains in the cytoplasmic membrane of microbes. The domain formation in the microbial membrane allows alexidine to cause significantly faster alteration in membrane permeability leading to more rapid bactericidal effect as compared to chlorhexidine.
  • Alexidine has also shown to promote apoptosis as an anti-cancer agent and possess antiinflammatory, and antidiabetic properties, which can aid in rapid wound healing. Furthermore, Alexidine is also shown to have significantly lower risk of causing IgE
  • Immunoglobulin E mediated hypersensitivity as compared to chlorhexidine.
  • the implantable orthopedic devices and antimicrobial coatings disclosed herein are directed at overcoming one or more of these disadvantages in currently available orthopedic devices.
  • an implantable orthopedic device having an antimicrobial coating on at least one surface thereof is disclosed.
  • the antimicrobial coating includes alexidine and a carrier polymer.
  • alexidine includes alexidine, aiexidine base, alexidme hydrochloride, alexidine dihydrochloride, alexidine monoacetate, alexidine diacetate, alexidine gluconate, alexidine digluconate and mixtures thereof.
  • alexidine used in the antimicrobial composition may be prepared by any of the processes known in the art for manufacturing alexidine.
  • antimicrobial agent may, in one aspect, refer to, without limitation, agent(s) that are responsible for, or cause the destruction and removal of viable microorganisms from a material including the biofilms and spores of the microorganisms.
  • the antimicrobial agent may, also without limitation, refer to agents that effect a reduction of viable microorganisms and their spores and does not necessarily imply the complete removal of all viable microorganisms and their spores.
  • hypoallergenic refers to a reduced allergic reaction or a reduced tendency to trigger hypersensitivity responses to allergens and may be mediated by IgE (Immunoglobulin E) antibodies.
  • IgE Immunoglobulin E
  • orthopedic device refers to medical devices that are used in orthopedic applications and may include without limitation rods, screws, pins, anchors, cages, and combinations thereof.
  • the term “implantable” refers to an orthopedic device to be positioned partially or wholly at a location within a body, such as within a body vessel. Additionally, the terms “implantation” and “implanted” refer to the positioning of a medical device at a location, partially or wholly, within a body, such as within a body vessel.
  • minimum inhibitory concentration and “MIC” are used interchangeably and refer to the minimum concentration of an antibacterial agent in a given culture medium below which bacterial growth is not inhibited.
  • minimum bactericidal concentration or “MBC” are used interchangeably and refer to the minimum concentration of an antibacterial agent in a given culture medium below which bacterial growth is not eliminated.
  • the present disclosure makes use of alexidine in an antimicrobial coating that is used to coat at least one surface of an implantable orthopedic device.
  • the antimicrobial coating comprises alexidine as an antimicrobial agent and a carrier polymer.
  • the duration of implantation of the orthopedic device disclosed herein may be permanent or may intend to remain in place for the remaining life span of the patient or until the orthopedic device is physically removed from the patient.
  • antimicrobial effects obtained from antimicrobial coatings of the present disclosure which include alexidine far exceed the results obtained from comparative antimicrobial coatings, which include chlorhexidine.
  • the antimicrobial coating has a broad spectrum antimicrobial effect against the gram positive bacteria, gram negative bacteria, and fungal pathogens responsible for infections.
  • the antimicrobial coating is effective against gram positive bacteria such as Staphylococcus aureus, gram negative bacteria such as Pseudomonas aeruginosa or fungi such as Candida albicans in both planktonic and biofilm forms, and to various extents. Therefore, methods of using the antimicrobial coating and the implantable orthopedic device described herein may be provided for the prevention and treatment of infections caused by these microorganisms.
  • the antimicrobial coating of the present disclosure may provide immediate and sustained delivery of alexidine to the tissues surrounding the implantable orthopedic device. Therefore, use of these implantable orthopedic devices may be effective in protecting the patient's body against pathogenic organisms.
  • the antimicrobial coating may further include various therapeutic agents.
  • the therapeutic agents may include, without limitation an antibiotic, anaesthetic, analgesic, anti-inflammatory agent, bone density increasing agents, or mixtures thereof.
  • the antimicrobial coating may improve bone density.
  • the antimicrobial coating may promote wound healing. Wound healing may be achieved through the use of alexidine alone or the incorporation of other suitable agents into the antimicrobial coating known in the art to promote wound healing.
  • a surprising and unexpected finding of the antimicrobial composition disclosed herein is that it has been shown to be hypoallergenic, in particular as compared to antimicrobial compositions based on chlorhexidine.
  • the antimicrobial composition may also be less likely to cause adverse reactions such as hypersensitivity and allergy. Methods and devices for the detection of allergic reactions and responses are described in U.S. Patent Application Publication No. 2014/0187892, the contents of which are incorporated herein by reference in their entirety.
  • the antimicrobial composition may also aid in reducing inflammatory responses such as erythema, phlebitis, and intimal hyperplasia.
  • the antimicrobial coating may include one or more of alexidine, alexidine base, alexidine hydrochloride, alexidine dihydrochloride, alexidine monoacetate, alexidine diacetate, alexidine gluconate, alexidine digluconate and mixtures thereof.
  • the alexidine used in the antimicrobial coating may be prepared by any of the processes known in the art for manufacturing alexidine.
  • One advantage of the antimicrobial coating of the present disclosure is that a greater antimicrobial effect is achieved using a lower concentration of alexidine than other antimicrobial agents, such as chlorhexidine.
  • the antimicrobial coating may have a concentration ranging from 0.0001 wt % to 4.0 wt % of alexidine. In another aspect, the antimicrobial coating may have a concentration ranging from 0.01 wt % to 2.0 wt % of alexidine. In another aspect, the antimicrobial coating may have a concentration of at least about 0.05 wt % of alexidine. The concentration of alexidine in the antimicrobial coating, however, is not limited in the present disclosure. The preferred amount of the antimicrobial coating on the orthopedic device may vary, depending on the nature of the orthopedic device and the nature of the implantation area.
  • the antimicrobial coating may not include chlorhexidine, triclosan, or silver.
  • alexidine may be the only antimicrobial agent present in the antimicrobial coating.
  • a solvent may be used in the antimicrobial coating.
  • the solvent may include water, an organic solvent, or any combination thereof. Suitable organic solvents, for example, may include without limitation, alcohol, dimethyl formamide, tetrahydrofuran (THF), ethyl acetate, butyl acetate, acetone, methyl ethyl ketone (MEK), citric acid, or mixtures thereof.
  • the solvent is one in which both the carrier polymer and alexidine are soluble.
  • the solvent used in the antimicrobial coating is an alcohol, such as isopropanol, methanol or ethanol or mixtures thereof.
  • the solvent may comprise tetrahydrofuran (THF) and methanol, THF and ethanol, or THF and isopropyl alcohol, or THF and citric acid, or THF and isopropyl alcohol and citric acid.
  • THF tetrahydrofuran
  • the antimicrobial coating includes a carrier polymer.
  • the carrier polymer generally includes a polymer that is soluble in alexidine.
  • the carrier polymer may also be a biocompatible polymer that does not have any detrimental effect on the antimicrobial properties of alexidine.
  • the carrier polymer may be a polymer that does not adversely affect the integrity of the orthopedic device in any manner.
  • Suitable carrier polymers include without limitation, polyurethane, polypropylene, polyester, cellulose, poly(methyl methacrylate), acrylate, or combinations, thereof.
  • the carrier polymer is polyurethane.
  • orthopedic devices especially suited for application of the antimicrobial coatings of this disclosure include, without limitation orthopedic implants such as joint prostheses, screws, nails, nuts, bolts, plates, rods, pins, wires, inserters, osteoports, halo systems and other orthopedic devices used for stabilization or fixation of spinal and long bone fractures or disarticulations.
  • orthopedic implants such as joint prostheses, screws, nails, nuts, bolts, plates, rods, pins, wires, inserters, osteoports, halo systems and other orthopedic devices used for stabilization or fixation of spinal and long bone fractures or disarticulations.
  • the orthopedic device may be composed of a metallic material, a non-metallic material such as a polymer material or a ceramic, or a combination thereof.
  • Suitable metallic materials may include for example, stainless steel, titanium, chromium, cobalt and alloys thereof.
  • Suitable polymer materials or non-metallic materials may include rubber, plastic, nylon, silicone, polyurethane, polyethylene, polyvinyl chloride, polytetrafluoroethylene tetraphthalate, polyethylene tetraphthalate, polytetrafluoroethylene, latex, and elastomers.
  • the antimicrobial coatings of the present discl osure may be prepared by any means known to those skilled in the art.
  • an antimicrobial coating solution may be prepared by mixing the alexidine and the carrier polymer with a solvent.
  • the antimicrobial coating solution may then be applied to at least portion of the orthopedic device, and then all owing the coating solution to dry or cure to form the antimicrobial coating.
  • the coating solution may be applied to the orthopedic device using any means known to those skilled in the art.
  • the antimicrobial coating solution may be sprayed onto surfaces of the orthopedic device.
  • the orthopedic device may be dipped into the antimicrobial coating solution to form a coating, or may be brush coated, die coated, wiped, painted, or rolled onto the surfaces of the orthopedic device.
  • extrusion methods may be useful to form either an antimicrobial layer on the orthopedic device or for bulk distribution of alexidine in the device. Any of these techniques or methods of applying the antimicrobial coating solution may be used in combination and/or repeated multiple times to form the desired antimi crobial coating,
  • the orthopedic device may be soaked in the antimicrobial coating solution for a period of time of about 5 seconds to about 5 minutes. In another aspect, the orthopedic device may be soaked in the antimicrobial coating solution for a period of time of about 2 seconds to about 2 minutes. In certain aspects, the orthopedic device is soaked in the antimicrobial coating solution for at least 4 seconds. However, the orthopedic device may be soaked in the antimicrobial coating solution for longer periods of time without adversely affecting the integrity of the orthopedic device.
  • the antimicrobial coating composition is a rapid disinfectant. This advantage is particularly valuable during orthopedic implant procedures where it is necessary to immediately facilitate sterilization and/or disinfection of the orthopedic implant itself, the implantation site and also its surroundings.
  • the orthopedic device may be dried at room temperature such that the solvent evaporates.
  • the orthopedic device may be dried by removing the solvent from the antimicrobial coating composition.
  • the solvent may be removed from the antimicrobial coating composition and an amount of alexidine may remain on a surface of the orthopedic device. The remaining amount of alexidine on the orthopedic device may provide an antimicrobial effect to the orthopedic device, which will serve to further prevent infection during the orthopedic procedure and in some cases, after the orthopedic procedure.
  • the alexidine may remain on the surface of the orthopedic device in its free form. Alternatively, the alexidine may become embedded in the matrix of the carrier polymer, which may provide a longer term antimicrobial effect for the patient through the orthopedic device.
  • the antimicrobial coating composition may be infused, absorbed, penetrated, coated, adhered into or onto a surface of the orthopedic device.
  • EXAMPLE 1 Composition of antimicrobial solution containing Chlorhexidine
  • An antimicrobial solution was prepared having the formulation shown in Table A.
  • EXAMPLE 2 Composition of antimicrobial solution containing Alexidine
  • An antimicrobial solution was prepared having the formulation shown in Table B.
  • EXAMPLE 3 Composition to make antimicrobial coating for an orthopedic device.
  • a coating solution having the formulation shown in Table C was prepared for application on orthopedic self-drilling pins composed of stainless steel or titanium material.
  • EXAMPLE 4 Antimicrobial performance of the self-drilling pins prepared as in Example 3.
  • Uncoated control and Alexidine coated orthopedic pins of either stainless steel or titanium material were placed into screw cap tubes. Staphylococcus aureus in Trypticase Soy Broth at a concentration of 3.0 x 10 3 CFU/ml was added to each tube at a volume large enough to cover the entire pin (7-9ml). The pins were incubated in the inoculated broth under static conditions at 37°C. Each day, an aliquot of ⁇ was removed from the broth, serially diluted in 0.85% saline, and plated on Dey Engley Neutralizing (D/E) Agar. After 24 hours, the resulting colonies, if any, were counted and recorded. Sampling was done over a period of 11 days.
  • the pins were transferred to freshly inoculated tubes of Staphylococcus aureus containing 10 CFU/ml. Post the 24 hour incubation (Day 12), the pins were removed from the broth, gently rinsed in 0.85% saline, and placed into tubes containing D/E broth. The pins were sonicated in the neutralizing broth for 20 minutes. The sonicated broth was then sampled and plated onto D/E agar. Plates were incubated for 24 hours at 37°C and colonies were counted and recorded.
  • EXAMPLE 5 Minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of Alexidine and Chlorhexidine.
  • dilution series was prepared in the wells of a 96-well plate by performing 1 : 1 dilutions to cover a concentration range of 0 - 512ppm.
  • Ten microliters from each of the drug concentration was mixed with 190 ⁇ of culture broth containing approximately 10 5 CFU/mL of bacteria or yeast species.
  • the test plate was incubated for 18 -24 hours after which absorbance of each well was read at 670nm on a BioTek plate reader.
  • the MIC value was the lowest concentration of the drug at which microbial growth was completely inhibited (with the absorbance reading at or below the reading of the drug control wells without any organisms).
  • the wells containing growth should have had higher absorbance reading when compared to the drug control wells. After reading the absorbance for the MIC, ⁇ of each test well was plated onto the surface of D/E agar in 6 or 12 well microtiter plates to determine the MBC. The plates were incubated inverted at 37°C for 24-48 hours after which numbers of colonies were counted. The MBC value was the lowest concentration of the drug at which no growth was observed.
  • Alexidine and Chlorhexidine both at a concentration of 128 ppm were exposed to a Gram positive bacteria ⁇ Staphylococcus aureus), a Gram negative bacteria ⁇ Pseudomonas aeruginosa), and a fungus ⁇ Candida albicans).
  • the challenge concentration for each organism was 10 4 - 10 5 CFU/mL, and the exposure time varied from 0.5 - 60 minutes.
  • Table H below shows the Time to Kill results for both Alexidine and Chlorhexidine. Complete kill of all three organisms was observed within 0.5 -1 minute of Alexidine exposure. In contrast, with Chlorhexidine it took 60 minutes before complete kill was observed for C. albicans and S. aureus, and 5 minutes for P. aeruginosa.
  • TNTC Number of microbial colonies were Too Numerous to Count
  • Example 3 The biocompatibility and toxicity of the antimicrobial compositions of Example 3 were assessed using the six tests described below. The test results show no adverse effects and demonstrate the safety and biocompatibility of surgical devices treated with alexidine. These results surprisingly further show that the antimicrobial composition is hypoallergenic.
  • EXAMPLE 7 The Intracutaneous Injection Test (ISO) was performed. Test rabbits received an intracutaneous injection of the antimicrobial composition of Example 3. All test rabbits increased in body weight and showed no signs of toxicity at the 24 hour, 48 hour and 72 hour observation points.
  • ISO Intracutaneous Injection Test
  • EXAMPLE 8 The Kligman Maximization Test (ISO) was performed. The skin of guinea pigs was treated with the test article extract and exhibited no reaction to the challenge (0% sensitization).
  • EXAMPLE 9 A 28 day Systemic Toxicity via Intramuscular Implantation was performed. The test articles did not demonstrated any local or systemic signs of toxicity when test articles composed of the antimicrobial composition of Example 3 was implanted into the muscle tissue of five rats for 28 days.
  • EXAMPLE 10 The Intramuscular Implantation Test (ISO) was performed. Macroscopic evaluation of the test article implantation site indicated no significant signs of inflammation, encapsulation, hemorrhage, or necrosis. However, microscopic evaluation (histology) of these sites indicated moderate reactivity when compared to the control sites having no implantation.
  • ISO Intramuscular Implantation Test
  • EXAMPLE 11 Intravascular implantation in a Sheep Model to determine safety and efficacy was performed.
  • the test device composed of the antimicrobial composition disclosed in Example 3 was well tolerated. All test animals remained healthy for the entire 7 and 30 day study duration and no signs of organ toxicity were observed.
  • Alexidine-treated device was highly effective in reducing colonization by Staphylococcus aureus (the challenge organism used to infect the implantation site) on the device and the vein tissue surrounding the device. As compared to the un-treated control device, Alexidine-treated device led to 7 to 8 Logio reduction in bacterial colonization on the device and the surrounding tissue.
  • Alexidine-treated device also led to 99% reduction in weight and 92% reduction in length of the device-associated thrombus when compared to the un-treated control device. There was also significant reduction in inflammatory response from the alexidine treated device compared to the untreated device.
  • EXAMPLE 12 The hemolytic index (HI) of the antimicrobial composition of Example 3 was also tested. The HI of the antimicrobial composition of Example 3 was shown to be comparable to chlorhexidine.

Abstract

La présente invention concerne un dispositif orthopédique implantable présentant un revêtement antimicrobien sur au moins une de ses surfaces. Le revêtement antimicrobien comprend de l'alexidine et un polymère de support.
PCT/US2016/043533 2015-07-24 2016-07-22 Dispositifs orthopédiques implantables présentant des revêtements antimicrobiens WO2017019494A1 (fr)

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US15/746,990 US20180221546A1 (en) 2015-07-24 2016-07-22 Implantable orthopedic devices having antimicrobial coatings
JP2018523377A JP2018520838A (ja) 2015-07-24 2016-07-22 抗菌コーティングを有する埋め込み型整形外科用装置
CN201680043187.0A CN107847647A (zh) 2015-07-24 2016-07-22 具有抗微生物涂层的可植入的矫形外科装置
EP16831118.1A EP3325034A4 (fr) 2015-07-24 2016-07-22 Dispositifs orthopédiques implantables présentant des revêtements antimicrobiens
HK18113695.1A HK1254710A1 (zh) 2015-07-24 2018-10-25 具有抗微生物塗層的可植入的矯形外科裝置

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US62/196,429 2015-07-24

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HK1254710A1 (zh) 2019-07-26
EP3325034A1 (fr) 2018-05-30

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